Published online ; Recent genetic studies have identified some alleles associated with higher BMI but lower risk of type 2 diabetes, hypertension and heart disease. These "favorable adiposity" alleles are collectively associated with lower insulin levels and higher subcutaneous-to-visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, test for interactions between BMI and favorable adiposity genetics and test effects separately in men and women.In the UK Biobank the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 Kg/m(2) [0.066,0.174]; p=1E-5) and higher body fat percentage (0.301 % [0.230,0.372]; p=1E-16) compared to the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favourable adiposity alleles were at: 0.837 OR [0.784,0.894] lower risk of type 2 diabetes (p=1E-7), -0.859 mmHg [-1.099,-0.618] lower systolic (p=3E-12) and -0.394 mmHg [-0.534,-0.254] lower diastolic blood pressure (p=4E-8), 0.935 OR [0.911,0.958] lower risk of hypertension (p=1E-7) and 0.921 OR [0.872,0.973] lower risk of heart disease (p=3E-3). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favourable body fat distribution, with a lower waist-hip ratio (-0.004 [-0.005,-0.003] 50% vs 50%; p=3E-14) but in men, the favourable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267,0.641] 50% vs 50%; p=2E-6) and higher waist-hip ratio (0.0013 [0.0003,0.0024] 50% vs 50%; p=0.01). Results were strengthened when meta-analysing with five additional studies. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score.In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. While higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk. ; S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). A.R.W. H.Y. and T.M.F. are supported by the European Research Council grant: 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. A.T.H. is a Wellcome Trust Senior Investigator and a National Institute of Health Research senior investigator. The Wellcome Trust provides support for GoDARTS (awards 072960/z/03/z and 099177/z12/z). The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). This work was performed as part of an ongoing collaboration of the PROSPER study group in the universities of Leiden, Glasgow and Cork. The research leading to these results has received funding from the Netherlands Consortium for Healthy Ageing (NCHA) and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PHASE. The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. Generation Scotland received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK’s Medical Research Council and the Wellcome Trust. Ethics approval for the study was given by the NHS Tayside committee on research ethics (reference 05/S1401/89). EPIC-Norfolk was funded by the Medical Research Council MC_UU_12015/1 and MC_PC_13048. E.P. holds a Wellcome Trust New Investigator award (102820/Z/13/Z ). The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.